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The final step in Notch signaling activation is the transmembrane cleavage of Notch receptor by γ secretase. Thus far, genetic and biochemical evidence indicates that four subunits are essential for γ secretase activity in vivo: presenilin (the catalytic core), APH-1, PEN-2, and APH-2/nicastrin. Although some γ secretase activity has been detected in APH-2/nicastrin-deficient mammalian cell lines, the lack of biological relevance for this activity has left the quaternary γ secretase model unchallenged. Here, we provide the first example of in vivo Notch signal transduction without APH-2/nicastrin. The surprising dispensability of APH-2/nicastrin is observed in Caenorhabditis elegans germline stem cells (GSCs) and contrasts with its essential role in previously described C. elegans Notch signaling events. Depletion of GLP-1/Notch, presenilin, APH-1, or PEN-2 causes a striking loss of GSCs. In contrast, aph-2/nicastrin mutants maintain GSCs and exhibit robust and localized expression of the downstream Notch target sygl-1. Interestingly, APH-2/nicastrin is normally expressed in GSCs and becomes essential under conditions of compromised Notch function. Further insight is provided by reconstituting the C. elegans γ secretase complex in yeast, where we find that APH-2/nicastrin increases but is not essential for γ secretase activity. Together, our results are most consistent with a revised model of γ secretase in which the APH-2/nicastrin subunit has a modulatory, rather than obligatory role. We propose that a trimeric presenilin-APH-1-PEN-2 γ secretase complex can provide a low level of γ secretase activity, and that cellular context determines whether or not APH-2/nicastrin is essential for effective Notch signal transduction., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: One-half of the 14 million persons in the US with knee osteoarthritis (OA) are not physically active, despite evidence that physical activity (PA) is associated with improved health. We undertook this study to estimate both the quality-adjusted life-year (QALY) losses in a US population with knee OA due to physical inactivity and the health benefits associated with higher PA levels., Methods: We used data from the Osteoarthritis Initiative and the Centers for Disease Control and Prevention to estimate the proportions of a US population with knee OA ages ≥45 years that are inactive, insufficiently active, and active, and the likelihood of a shift in their PA level. We used the OA Policy Model, a computer simulation of knee OA, to determine QALYs lost due to inactivity and to measure potential benefits of increased PA (comorbidities averted and QALYs saved)., Results: Among 13.7 million persons with knee OA, a total of 7.5 million QALYs, or 0.55 QALYs per person, were lost due to inactivity or insufficient PA relative to activity over their remaining lifetimes. Black Hispanic women experienced the highest losses, at 0.76 QALYs per person. Women of all races/ethnicities had ~20% higher loss burdens than men. According to our model, if 20% of the inactive population were instead active, 95,920 cases of cancer, 222,413 of cardiovascular disease, and 214,725 of diabetes mellitus would potentially be averted, and 871,541 potential QALYs would be saved., Conclusion: Physical inactivity leads to substantial QALY losses in a US population with knee OA. Increases in the activity levels in even a fraction of this population may have considerable collateral health benefits, potentially averting cases of cancer, cardiovascular disease, and diabetes mellitus., (© 2019, American College of Rheumatology.)

Objective: Type II diabetes mellitus (T2DM) is prevalent in knee osteoarthritis (OA) patients undergoing total knee arthroplasty (TKA) and increases risk for prosthetic joint infection (PJI). We examined the cost-effectiveness of antibiotic prophylaxis (AP) before dental procedures to reduce PJI in TKA recipients with T2DM., Design: We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare two strategies among TKA recipients with T2DM (mean age 68 years, mean BMI 35.4 kg/m 2 ): 1) AP before dental procedures and 2) no AP. Outcomes included quality-adjusted life expectancy (QALE) and lifetime medical costs. We used published efficacy of AP. We report incremental cost-effectiveness ratios (ICERs) and considered strategies with ICERs below well-accepted willingness-to-pay (WTP) thresholds cost-effective. We conducted sensitivity analyses to examine the robustness of findings to uncertainty in model input parameters. We used a lifetime horizon and healthcare sector perspective., Results: We found that AP added 1.0 quality-adjusted life-year (QALY) and $66,000 for every 1000 TKA recipients with T2DM, resulting in an ICER of $66,000/QALY. In sensitivity analyses, reduction of the probability of PJI, T2DM-associated risk of infection, or attribution of infections to dental procedures by 50% resulted in ICERs exceeding $100,000/QALY. Probabilistic sensitivity analyses showed that AP was cost-effective in 32% and 58% of scenarios at WTP of $50,000/QALY and $100,000/QALY, respectively., Conclusions: AP prior to dental procedures is cost-effective for TKA recipients with T2DM. However, the cost-effectiveness of AP depends on the risk of PJI and efficacy of AP in this population., Competing Interests: The authors do not report any competing interests., (© 2020 The Authors.)

Objective: Diet and exercise (D+E) for knee osteoarthritis (OA) is effective and cost-effective. However, cost-effectiveness does not imply affordability; the impact of knee OA-specific D+E programs on insurer budgets is unknown., Methods: We estimated changes in undiscounted medical expenditures (2016 US dollars) with and without a D+E program. We accounted for both additional program outlays and potential savings from reduced use of other knee OA treatments and from reduced incidence of comorbidities. We adopted the perspective of a representative commercial insurance plan covering 200 000 individuals aged 25 to 64 years and a representative Medicare Advantage plan covering 200 000 Medicare-eligible individuals aged 65 years and older. We used the Osteoarthritis Policy Model, a validated microsimulation model of knee OA, to model D+E efficacy (measured by pain and weight reduction), adherence, and price based on the Intensive Diet and Exercise for Arthritis (IDEA) trial. In sensitivity analyses, we varied time horizon, D+E efficacy, and D+E price., Results: Over 3 years, the D+E program increased spending by $752 200 ($0.10 per member per month [PMPM]) in the commercial plan and by $6.0 million ($0.84 PMPM) in the Medicare plan. Over 3 years, the D+E program reduced opioid use by 6% and 5% and reduced total knee replacements by 5% and 4% in the commercial and Medicare plans, respectively. Expenses were higher in the Medicare plan because it had more patients with knee OA than the commercial plan., Conclusion: Although there is no established threshold to define affordability, a D+E program for knee OA would likely produce expenditures comparable with outlays for other health-promotion interventions., (© 2019 Brigham and Women's Hospital. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: The Intensive Diet and Exercise for Arthritis (IDEA) trial showed that an intensive diet and exercise (D+E) program led to a mean 10.6-kg weight reduction and 51% pain reduction in patients with knee osteoarthritis (OA). The aim of the current study was to investigate the cost-effectiveness of adding this D+E program to treatment in overweight and obese (body mass index >27 kg/m 2 ) patients with knee OA., Methods: We used the Osteoarthritis Policy Model to estimate quality-adjusted life-years (QALYs) and lifetime costs for overweight and obese patients with knee OA, with and without the D+E program. We evaluated cost-effectiveness with the incremental cost-effectiveness ratio (ICER), a ratio of the differences in lifetime cost and QALYs between treatment strategies. We considered 3 cost-effectiveness thresholds: $50,000/QALY, $100,000/QALY, and $200,000/QALY. Analyses were conducted from health care sector and societal perspectives and used a lifetime horizon. Costs and QALYs were discounted at 3% per year. D+E characteristics were derived from the IDEA trial. Deterministic and probabilistic sensitivity analyses (PSAs) were used to evaluate parameter uncertainty and the effect of extending the duration of the D+E program., Results: In the base case, D+E led to 0.054 QALYs gained per person and cost $1,845 from the health care sector perspective and $1,624 from the societal perspective. This resulted in ICERs of $34,100/QALY and $30,000/QALY. In the health care sector perspective PSA, D+E had 58% and 100% likelihoods of being cost-effective with thresholds of $50,000/QALY and $100,000/QALY, respectively., Conclusion: Adding D+E to usual care for overweight and obese patients with knee OA is cost-effective and should be implemented in clinical practice., (© 2018, American College of Rheumatology.)

Objective: Total knee replacement (TKR) is an effective treatment for end-stage knee osteoarthritis (OA). American racial minorities undergo fewer TKRs than whites. We estimated quality-adjusted life-years (QALYs) lost for African American knee OA patients due to differences in TKR offer, acceptance, and complication rates., Methods: We used the Osteoarthritis Policy Model, a computer simulation of knee OA, to predict QALY outcomes for African American and white knee OA patients with and without TKR. We estimated per-person QALYs gained from TKR as the difference between QALYs with current TKR use and QALYs when no TKR was performed. We estimated average, per-person QALY losses in African Americans as the difference between QALYs gained with white rates of TKR and QALYs gained with African American rates of TKR. We calculated population-level QALY losses by multiplying per-person QALY losses by the number of persons with advanced knee OA. Finally, we estimated QALYs lost specifically due to lower TKR offer and acceptance rates and higher rates of complications among African American knee OA patients., Results: African American men and women gain 64,100 QALYs from current TKR use. With white offer and complications rates, they would gain an additional 72,000 QALYs. Because these additional gains are unrealized, we call this a loss of 72,000 QALYs. African Americans lose 67,500 QALYs because of lower offer rates, 15,800 QALYs because of lower acceptance rates, and 2,600 QALYs because of higher complication rates., Conclusion: African Americans lose 72,000 QALYs due to disparities in TKR offer and complication rates. Programs to decrease disparities in TKR use are urgently needed., (© 2018, American College of Rheumatology.)

Background: Inclement weather and home environment can act as barriers to physical activity. However, it is unclear if they reduce the activity of persons participating in activity-promoting programs., Methods: Data from a 6-month workplace financial incentives program were used to establish the association between meteorologic (temperature, rain, snow, and wind) and geographic factors (urban/nonurban home location and distance between home and work) and moderate to vigorous physical activity (MVPA). Multivariable models were built to estimate mean weekly minutes of MVPA adjusting for demographic factors, clinical factors, and impulsivity., Results: The 292 participants had a mean age of 38 (SD = 11) years. Eighty-three percent were female and 62% were white. Twenty-nine percent lived within 3 miles of work, and 35% lived in urban areas. Participants who lived more than 3 miles from work averaged 75 [95% confidence interval (CI), 65-84] minutes of weekly MVPA compared with 105 (95% CI, 88-122) minutes for those who lived within 3 miles of work. Urban participants averaged 70 (95% CI, 57-83) minutes of MVPA compared with 91 (95% CI, 80-102) minutes for nonurban participants. Colder temperatures were associated with decreased MVPA, and impulsivity modified the effect., Conclusions: Colder temperatures, greater distance from work, and an urban residence are associated with fewer minutes of MVPA.

Background: We designed and implemented the Brigham and Women's Wellness Initiative (B-Well), a single-arm study to examine the feasibility of a workplace program that used individual and team-based financial incentives to increase physical activity among sedentary hospital employees., Methods: We enrolled sedentary, non-clinician employees of a tertiary medical center who self-reported low physical activity. Eligible participants formed or joined teams of three members and wore Fitbit Flex activity monitors for two pre-intervention weeks followed by 24 weeks during which they could earn monetary rewards. Participants were rewarded for increasing their moderate-to-vigorous physical activity (MVPA) by 10% from the previous week or for meeting the Centers for Disease Control and Prevention (CDC) physical activity guidelines (150 min of MVPA per week). Our primary outcome was the proportion of participants meeting weekly MVPA goals and CDC physical activity guidelines. Secondary outcomes included Fitbit-wear adherence and factors associated with meeting CDC guidelines more consistently., Results: B-Well included 292 hospital employees. Participants had a mean age of 38 years (SD 11), 83% were female, 38% were obese, and 62% were non-Hispanic White. Sixty-three percent of participants wore the Fitbit ≥4 days per week for ≥20 weeks. Two-thirds were satisfied with the B-Well program, with 79% indicating that they would participate again. Eighty-six percent met either their personal weekly goal or CDC physical activity guidelines for at least 6 out of 24 weeks, and 52% met their goals or CDC physical activity guidelines for at least 12 weeks. African Americans, non-obese subjects, and those with lower impulsivity scores reached CDC guidelines more consistently., Conclusions: Our data suggest that a financial incentives-based workplace wellness program can increase MVPA among sedentary employees. These results should be reproduced in a randomized controlled trial., Trial Registration: Clinicaltrials.gov, NCT02850094 . Registered July 27, 2016 [retrospectively registered].

Objective: Young adults, in general, are not aware of their risk of knee osteoarthritis (OA). Understanding risk and risk factors is critical to knee OA prevention. We tested the efficacy of a personalized risk calculator on accuracy of knee OA risk perception and willingness to change behaviors associated with knee OA risk factors., Methods: We conducted a randomized controlled trial of 375 subjects recruited using Amazon Mechanical Turk. Subjects were randomized to either use a personalized risk calculator based on demographic and risk-factor information (intervention), or to view general OA risk information (control). At baseline and after the intervention, subjects estimated their 10-year and lifetime risk of knee OA and responded to contemplation ladders measuring willingness to change diet, exercise, or weight-control behaviors., Results: Subjects in both arms had an estimated 3.6% 10-year and 25.3% lifetime chance of developing symptomatic knee OA. Both arms greatly overestimated knee OA risk at baseline, estimating a 10-year risk of 26.1% and a lifetime risk of 47.8%. After the intervention, risk calculator subjects' perceived 10-year risk decreased by 12.9 percentage points to 12.5% and perceived lifetime risk decreased by 19.5 percentage points to 28.1%. Control subjects' perceived risks remained unchanged. Risk calculator subjects were more likely to move to an action stage on the exercise contemplation ladder (relative risk 2.1). There was no difference between the groups for diet or weight-control ladders., Conclusion: The risk calculator is a useful intervention for knee OA education and may motivate some exercise-related behavioral change., (© 2016, American College of Rheumatology.)

Background: Although community-based adaptive sports have become a popular means of rehabilitation for individuals with disabilities, little is known regarding the factors that lead to sustained participation., Objective: To determine the demographic, environmental, disability-related, and functional factors associated with sustained participation in a community-based adaptive sports program., Design: Retrospective cohort study., Setting: Community-based adaptive sports program., Participants: Adults with mobility-related disabilities., Methods: Data were collected from registration forms and participation logs. Participants were described as "sustainers" if they attended ≥2 sessions, or as "nonsustainers" if they attended 0 or 1 session. We examined the associations between sustained participation and demographic, environmental, disability-related, and functional factors in bivariate and multivariable analyses., Main Outcome Measurement: Sustained participation in the adaptive sports program., Results: Of the 134 participants, 78 (58%) were sustainers and 56 (42%) were nonsustainers. In multivariable analyses, participants who ambulated independently had lower odds of being sustainers (odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.11, 0.96), and those who used an ambulatory assistive device had twice the odds of being sustainers (OR = 2.0, 95% CI = 0.65, 6.2) compared to those who used a manual wheelchair. Moreover, participants who lived within 5.3 miles of the program site (OR = 3.8, 95% CI = 1.1, 13.0) and those who lived between 5.3 and 24.4 miles from the program site (OR = 2.8, 95% CI = 1.0, 7.7) had significantly higher odds of sustained participation than those who lived more than 24.4 miles from the program site., Conclusion: Sustained participation in community-based adaptive sports is associated with living closer to the program site and the presence of a moderate level of functional impairment. These findings suggest that programs might consider increasing the number of satellite sites and expanding offerings for individuals with mild or more significant mobility-related disabilities to effectively increase program participation., Level of Evidence: II., (Copyright © 2017 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)